Antiviral indoles

ABSTRACT

Compounds of the formula (I): 
     
       
         
         
             
             
         
       
     
     wherein A, B, D, M, Ar, W, X, Y, Z and R 1  are as defined herein, are useful in the prevention and treatment of hepatitis C infections. The compounds, their preparation, pharmaceutical compositions containing them and their use in medicine are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to British Provisional application GB0625349.6, filed Dec. 20, 2006, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to macrocyclic indole compounds, topharmaceutical compositions containing them, to their use in theprevention and treatment of hepatitis C infections and to methods ofpreparation of such compounds and compositions.

BACKGROUND OF THE INVENTION

Hepatitis C(HCV) is a cause of viral infections. There is as yet noadequate treatment for HCV infection but it is believed that inhibitionof its RNA polymerase in mammals, particularly humans, would be ofbenefit.

Published International patent application WO 2005/080399 (Japan TobaccoInc.) discloses the following fused heterotetracyclic compounds:

where A, X, Cy, G¹, G², G³, G⁴, G⁵, G⁶, R¹, R², R³, R⁴, R⁵, R⁶ and a aredefined therein, and their use as HCV polymerase inhibitors.

Published International patent application WO 2006/020082 (Bristol-MyersSquibb Company) discloses the following fused tetracyclic compounds:

where A, B, R¹, R², R³ and n are defined therein, and their use intreating hepatitis C.

Published International applications WO 2006/046030 and WO 2006/046039(both Istituto Di Ricerche Di Biologia Molecolare P. Angeletti SpA)disclose certain tetracyclic indole derivatives:

wherein R¹, R², A, Ar, W, X, Y, and Z are defined therein, useful forthe treatment or prevention of infection by hepatitis C virus.

SUMMARY OF THE INVENTION

Thus, the present invention provides the compound of the formula (I):

wherein

Ar is a moiety containing at least one aromatic ring and possesses 5-,6-, 9- or 10-ring atoms optionally containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, which ring is optionallysubstituted by groups Q¹ and Q²;

Q¹ is halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, aryl, heteroaryl,CONR^(a)R^(b), (CH₂)₀₋₃NR^(a)R^(b), O(CH₂)₁₋₃NR^(a)R^(b),O(CH₂)₀₋₃CONR^(a)R^(b), O(CH₂)₀₋₃aryl, O(CH₂)₀₋₃heteroaryl,O(CR^(e)R^(f))aryl, O(CR^(e)R^(f))heteroaryl or OCHR^(c)R^(d);

R^(a) and R^(b) are each independently selected from hydrogen, C₁₋₄alkyland C(O)C₁₋₄alkyl;

or R^(a), R^(b) and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms, where said ring is optionallysubstituted by halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy;

R^(c) and R^(d) are each independently selected from hydrogen andC₁₋₄alkoxy;

or R^(c) and R^(d) are linked by a heteroatom selected from N, O and Sto form a heteroaliphatic ring of 4 to 7 ring atoms, where said ring isoptionally substituted by halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy;

and wherein said C₁₋₄alkyl, C₁₋₄alkoxy and aryl groups are optionallysubstituted by halogen or hydroxy;

R^(e) is hydrogen or C₁₋₆alkyl;

R^(f) is C₁₋₆alkyl;

Q² is halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy, where said C₁₋₄alkyland C₁₋₄alkoxy groups are optionally substituted by halogen or hydroxy;

or Q¹ and Q² may be linked by a bond or a heteroatom selected from N, Oand S to form a ring of 4 to 7 atoms, where said ring is optionallysubstituted by halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy;

A is C₃₋₆alkyl or C₂₋₆alkenyl,

or A is a non-aromatic ring of 3 to 8 ring atoms where said ring maycontain a double bond and/or may contain a O, S, SO, SO₂ or NH moiety,

or A is a non-aromatic bicyclic moiety of 4 to 8 ring atoms,

and A is optionally substituted by halogen, hydroxy, C₁₋₄alkyl orC₁₋₄alkoxy;

D is N or CR⁹;

R^(g) is hydrogen, fluorine, chlorine, C₁₋₄alkyl, C₂₋₄alkenyl orC₁₋₄alkoxy, where said C₁₋₄alkyl, C₂₋₄alkenyl and C₁₋₄alkoxy groups areoptionally substituted by hydroxy or fluorine;

W is a bond, C═O, O, S(O)₀₋₂ or —(CR¹⁰R¹¹)—(CR¹²R¹³)₀₋₁—;

X is C═O, O, —CR¹⁴R¹⁵— or NR¹⁴;

R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are each independently selected fromhydrogen, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, C(O)C₁₋₆alkyl,(CH₂)₀₋₃aryl, (CH₂)₀₋₃heteroaryl, (CH₂)₀₋₃Het, (CH₂)₀₋₃NR¹⁶R¹⁷,C(O)(CH₂)₀₋₃NR¹⁶R¹⁷, NHC(O)(CH₂)₀₋₃NR¹⁶R¹⁷, O(CH₂)₁₋₃NR¹⁶R¹⁷,S(O)₀₋₂(CH₂)₀₋₃R¹⁶R¹⁷ and C(O)(CH₂)₀₋₃OR¹⁶;

or R¹⁴ is linked to R² or R²³ to form a ring of 4 to 10 atoms, wheresaid ring is optionally substituted by halogen, hydrogen, C₁₋₄alkyl orC₁₋₄alkoxy;

Het is a heteroaliphatic ring of 4 to 7 ring atoms, which ring maycontain 1, 2 or 3 heteroatoms selected from N, O or S or a group S(O),S(O)₂, NH or NC₁₋₄alkyl;

R¹⁶ and R¹⁷ are independently selected from hydrogen, C₁₋₆alkyl and(CH₂)₀₋₄NR¹⁸R¹⁹; or R¹⁶, R¹⁷ and the nitrogen atom to which they areattached form a heteroaliphatic ring of 4 to 7 ring atoms, which ringmay optionally contain 1 or 2 more heteroatoms selected from O or S or agroup S(O), S(O)₂, NH or NC₁₋₄alkyl, and which ring is optionallysubstituted by halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy;

R¹⁸ and R¹⁹ are independently selected from hydrogen and C₁₋₆alkyl; orR¹⁸, R¹⁹ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms, which ring may optionallycontain 1 or 2 more heteroatoms selected from O or S or a group S(O),S(O)₂, NH or NC₁₋₄alkyl, and which ring is optionally substituted byhalogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy;

R¹ is hydrogen or C₁₋₆alkyl;

B is —CR²⁰R²¹—, —C(═O)—, —SO— or —SO₂—;

R²⁰ and R²¹ are independently selected from hydrogen and C₁₋₆alkyl; orR²⁰ and R²¹, together with the carbon atom to which they are joined,form a C₃₋₆cycloalkyl group;

M is C₄₋₈alkylene or C₄₋₈alkenylene, optionally substituted by R²²,where 1, 2 or 3 of the carbon atoms in the C₄₋₈alkylene orC₄₋₈alkenylene groups is optionally replaced by O, NR²³, S, SO, SO₂,aryl, heteroaryl or Het,

where R²³ is hydrogen or C₁₋₆alkyl,or R²³ is linked to R¹⁴ to form a ring of 4 to 10 atoms as hereinbeforedescribed;where R²² is halo, C₁₋₄alkyl, (CH₂)₀₋₃C₃₋₈cycloalkyl, (CH₂)₀₋₃aryl,heteroaryl, Het or oxo,or R²² is linked to R¹⁴ to form a ring of 4 to 10 atoms as hereinbeforedescribed;and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention, Ar is a five- orsix-membered aromatic ring optionally containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, and which ring is optionallysubstituted by groups Q¹ and Q² as hereinbefore defined.

Preferably, Ar is a five- or six-membered aromatic ring optionallycontaining 1 or 2 heteroatoms independently selected from N, O or S,such as phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl,pyrazolyl, imidazolyl and thienyl, which ring is optionally substitutedby groups Q¹ and Q² as hereinbefore defined. More preferably, Ar isphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl or 3-furanyl,particularly phenyl, optionally substituted by groups Q¹ and Q² ashereinbefore defined.

Preferably, Q¹ is halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy. Morepreferably, Q¹ is fluorine, chlorine, methyl or methoxy. Mostpreferably, Q¹ is methoxy.

Preferably, Q² is absent.

In a further embodiment, A is C₃₋₆alkyl, C₂₋₆alkenyl or C₃₋₈cycloalkyl,where A is optionally substituted by halogen, hydroxy, C₁₋₄alkyl orC₁₋₄alkoxy. Preferably, A is C₃₋₈cycloalkyl, more preferably cyclopentylor cyclohexyl, most preferably cyclohexyl, optionally substituted byhalogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy.

Preferably, A is unsubstituted or substituted by fluorine, chlorine,methyl or methoxy, particularly fluorine. More preferably, A isunsubstituted.

In a further embodiment, D is CR^(g) where R^(g) is as hereinbeforedefined. Preferably, R^(g) is hydrogen or C₁₋₄alkyl. More preferably,R^(g) is hydrogen.

In a further embodiment, W is a bond, C═O or —(CR¹⁰R¹¹)—(CR¹²R¹³)₀₋₁—where R¹⁰, R¹¹, R¹² and R¹³ are as hereinbefore defined. Preferably, Wis —(CR¹⁰R¹¹)—(CR¹²R¹³)₀₋₁—. More preferably, W is —CH₂— or —CH₂CH₂—.Most preferably, W is —CH₂—.

In a further embodiment, X is C═O or —CR¹⁴R¹⁵, where R¹⁴ and R¹⁵ are ashereinbefore defined. Preferably, X is C═O or —CH₂—.

In a further embodiment, R¹ is hydrogen or methyl. Preferably, R¹ ishydrogen.

In a further embodiment, B is —CH₂— or —SO₂—. Preferably, B is —SO₂—.

In a further embodiment, M is C₄₋₈alkylene, optionally substituted byhalo, C₁₋₄alkyl or oxo, where 1 or 2 of the carbon atoms in theC₄₋₈alkylene group is optionally replaced by O, NR²³, S, SO or SO₂,where R²³ is as hereinbefore defined. Preferably, M is C₅₋₈alkylene,optionally substituted by C₁₋₄alkyl or oxo, where 1 or 2 of the carbonatoms in the C₅₋₈alkylene group is replaced by O, NH or N(C₁₋₄alkyl).Examples of suitable M groups include:

In one embodiment of the present invention, there is provided thecompound of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein W, X and M are asdefined in relation to formula (I).

When any variable occurs more than one time in formula (I) or in anysubstituent, its definition on each occurrence is independent of itsdefinition at every other occurrence.

As used herein, the term “alkyl” or “alkoxy” as a group or part of agroup means that the group is straight or branched. Examples of suitablealkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyland t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

The cycloalkyl groups referred to herein may represent, for example,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein, the term “alkenyl” and “alkynyl” as a group or part of agroup means that the group is straight or branched. Examples of suitablealkenyl groups include vinyl and allyl. A suitable alkynyl group ispropargyl.

As used herein, the term “alkylene” means that the alkyl group links twoseparate groups and may be straight or branched. Examples of suitablealkylene groups include ethylene [—CH₂—CH₂—] and propylene[—CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂— or —CH₂—CH(CH₃)—]. The terms “alkenylene”and “alkynylene” shall be construed in an analogous manner.

When used herein, the term “halogen” means fluorine, chlorine, bromineand iodine.

When used herein, the term “aryl” as a group or part of a group means acarbocyclic aromatic ring. Examples of suitable aryl groups includephenyl and naphthyl.

When used herein, the term “heteroaryl” as a group or part of a groupmeans a 5- to 10-membered heteroaromatic ring system containing 1 to 4heteroatoms selected from N, O and S. Particular examples of such groupsinclude pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl,tetrazolyl, indolyl, benzothienyl, benzimidazolyl, benzofuryl,quinolinyl and isoquinolinyl.

Where a compound or group is described as “optionally substituted” oneor more substituents may be present. Furthermore, optional substituentsmay be attached to the compounds or groups which they substitute in avariety of ways, either directly or through a connecting group of whichthe following are examples: amine, amide, ester, ether, thioether,sulfonamide, sulfamide, sulfoxide, urea, thiourea and urethane. Asappropriate an optional substituent may itself be substituted by anothersubstituent, the latter being connected directly to the former orthrough a connecting group such as those exemplified above.

Specific compounds within the scope of this invention include:

-   101:    16-cyclohexyl-3,6-dimethyl-17-phenyl-4,5,6,7,8,9-hexahydro-1H-13,15-(ethanediylidene)pyrrolo[2,1-f][1,2,7,10,13]thiatetraazacyclohexadecine-2,12(3H)-dione    10,10-dioxide,-   201:    17-cyclohexyl-3,6-dimethyl-18-phenyl-3,4,5,6,7,8,9,10-octahydro-14,16-(ethanediylidene)pyrrolo[2,1-f][1,2,7,10,13]thiatetraazacycloheptadecine-2,13-dione    11,11-dioxide,    and pharmaceutically acceptable salts thereof.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable acid such as hydrochloric acid, fumaricacid, p-toluenesulfonic acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the “parent drug” or “parent molecule”)that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulfate ester, or reduction oroxidation of a susceptible functionality.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The present invention also includes within its scope any enantiomers,diastereomers, geometric isomers and tautomers of the compounds offormula (I). It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the invention.

The present invention further provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in therapy.

In another aspect, the invention provides the use of a compound offormula (I) as defined above, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for treatment or preventionof infection by hepatitis C virus in a human or animal.

A further aspect of the invention provides a pharmaceutical compositioncomprising a compound of formula (I) as defined above, or apharmaceutically acceptable salt thereof, in association with apharmaceutically acceptable carrier. The composition may be in anysuitable form, depending on the intended method of administration. Itmay for example be in the form of a tablet, capsule or liquid for oraladministration, or of a solution or suspension for administrationparenterally.

The pharmaceutical compositions optionally also include one or moreother agents for the treatment of viral infections such as an antiviralagent, or an immunomodulatory agent such as α-, β- or γ-interferon.

In a further aspect, the invention provides a method of inhibitinghepatitis C virus polymerase and/or of treating or preventing an illnessdue to hepatitis C virus, the method involving administering to a humanor animal (preferably mammalian) subject suffering from the condition atherapeutically or prophylactically effective amount of thepharmaceutical composition described above or of a compound of formula(I) as defined above, or a pharmaceutically acceptable salt thereof.“Effective amount” means an amount sufficient to cause a benefit to thesubject or at least to cause a change in the subject's condition.

The dosage rate at which the compound is administered will depend on avariety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the age of the patient, body weight, general health, sex, diet, mode andtime of administration, rate of excretion, drug combination, theseverity of the particular condition and the host undergoing therapy.Suitable dosage levels may be of the order of 0.02 to 5 or 10 g per day,with oral dosages two to five times higher. For instance, administrationof from 1 to 50 mg of the compound per kg of body weight from one tothree times per day may be in order. Appropriate values are selectableby routine testing. The compound may be administered alone or incombination with other treatments, either simultaneously orsequentially. For instance, it may be administered in combination witheffective amounts of antiviral agents, immunomodulators, anti-infectivesor vaccines known to those of ordinary skill in the art. It may beadministered by any suitable route, including orally, intravenously,cutaneously and subcutaneously. It may be administered directly to asuitable site or in a manner in which it targets a particular site, suchas a certain type of cell. Suitable targeting methods are already known.

An additional aspect of the invention provides a method of preparationof a pharmaceutical composition, involving admixing at least onecompound of formula (I) as defined above, or a pharmaceuticallyacceptable salt thereof, with one or more pharmaceutically acceptableadjuvants, diluents or carriers and/or with one or more othertherapeutically or prophylactically active agents.

The present invention also provides a process for the preparation ofcompounds of formula (I).

According to a general process (a), compounds of formula (I) may beprepared by internal ring closure of the compound of formula (II):

where A, Ar, B, D, R¹, W and X are as defined in relation to formula(I), and M′ and M″ have suitable precursor functionality to form group Mas defined in relation to formula (I). For instance, when M is—CH₂—CH₂—CH₂—N(CH₃)—CH₂—CH₂—N(CH₃)—, M′ can be —CH₂—CH₂—CH₂Cl and M″ canbe —N(CH₃)—CH₂—CH₂—NH(CH₃), where the reaction is carried out in thepresence of a mild base, such as diisopropylethylamine, in a suitablesolvent, such as DMF, under microwave irradiation.

Compounds of formula (II) are either known in the art or may be preparedby conventional methodology well known to one of ordinary skill in theart using, for instance, procedures described in the accompanyingDescriptions and Examples, or by alternative procedures which will bereadily apparent.

General Synthetic Schemes

Two general strategies were employed for assembly of compounds from theuntethered macrocyclic class (Methods A and B); Method B can be regardedas an extension of Method A.

A suitably C2/C3 functionalised indole-6-carboxylate was assembled first(as described in published International applications WO 2004/087714 andWO 2006/029912). B′, W′ and X′ are suitable precursor functionality togroups B, W and X respectively as defined in relation to formula (I). Aprecursor fragment to one section of the macrocycle was installed on theindole N, with subsequent unmasking of the acid at C6 andfunctionalisation to introduce a precursor fragment to the remainingsegment of the macrocycle. Functional group manipulation andmacrocyclisation (e.g., via amide bond formation, alkylation, reductiveamination, metathesis etc.) set up the macrocycle. Potentially, the bondformed in ring closure can be at almost any point around the macrocycliclinker (e.g., forming the acylsulfonamide bond could also be the ringclosing step).

B′, M′, W′ and X′ have suitable precursor functionality to groups B, M,W and X respectively as defined in relation to formula (I). Functionalgroups on the macrocycle were manipulated post-closure, e.g., viareductive amination, alkylation, amide reduction, amide formation, etc.Potentially, sidechains can branch from any point around the macrocycliclinker.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3rd edition, 1999. The protecting groups may be removed ata convenient subsequent stage using methods known from the art.

The present invention is illustrated further by the followingnon-limiting examples.

The compounds of the invention were tested for inhibitory activityagainst the HCV RNA dependent RNA polymerase (NS5B) in an enzymeinhibition assay (example (i)) and in a cell based sub-genomicreplication assay (example (ii)). The compounds generally have IC50'sbelow 1 μM in the enzyme assay and several examples have EC50's below 5μM in the cell based assay.

Compound names in the examples were generated using software fromACDLabs (version 8.0).

(i) In-Vitro HCV NS5B Enzyme Inhibition Assay

WO 96/37619 describes the production of recombinant HCV RdRp from insectcells infected with recombinant baculovirus encoding the enzyme. Thepurified enzyme was shown to possess in vitro RNA polymerase activityusing RNA as template. The reference describes a polymerisation assayusing poly(A) and oligo(U) as a primer or an heteropolymeric template.Incorporation of tritiated UTP or NTPs is quantified by measuringacid-insoluble radioactivity. The present inventors have employed thisassay to screen the various compounds described above as inhibitors ofHCV RdRp.

Incorporation of radioactive UMP was measured as follows. The standardreaction (50 μl) was carried out in a buffer containing 20 mM tris/HClpH 7.5, 5 mM MgCl₂, 1 mM DTT, 50 mM NaCl, 0.03% N-octylglucoside, 1 μCi[³H]-UTP (40 Ci/mmol, NEN), 10 μM UTP and 10 μg/ml poly(A) or 5 μM NTPsand 5 μg/ml heteropolymeric template. Oligo(U)₁₂ (1 μg/ml, Genset) wasadded as a primer in the assay working on Poly(A) template. The finalNS5B enzyme concentration was 5 nM. The order of assembly was: 1)compound, 2) enzyme, 3) template/primer, 4) NTP. After 1 h incubation at22° C. the reaction was stopped by adding 50 μl of 20% TCA and applyingsamples to DE81 filters. The filters were washed thoroughly with 5% TCAcontaining 1M Na₂HPO₄/NaH₂PO₄, pH 7.0, rinsed with water and thenethanol, air dried, and the filter-bound radioactivity was measured inthe scintillation counter. Carrying out this reaction in the presence ofvarious concentrations of each compound set out above alloweddetermination of IC₅₀ values by utilising the formula:

% Residual activity=100/(1+[I]/IC ₅₀)^(s)

where [I] is the inhibitor concentration and “s” is the slope of theinhibition curve.

(ii) Cell Based HCV Replication Assay

Cell clones that stably maintain subgenomic HCV replicon were obtainedby transfecting Huh-7 cells with an RNA replicon identical toI₃₇₇neo/NS3-3′/wt described by Lohmann et al. (1999) (EMBL-GENBANK No.AJ242652), followed by selection with neomycin sulfate (G418). Viralreplication was monitored by measuring the expression of the NS3 proteinby an ELISA assay performed directly on cells grown in 96 wellsmicrotiter plates (Cell-ELISA) using the anti-NS3 monoclonal antibody10E5/24 (as described in published International application WO02/59321). Cells were seeded into 96 well plates at a density of 10⁴cells per well in a final volume of 0.1 ml of DMEM/10% FCS. Two hoursafter plating, 50 μl of DMEM/10% FCS containing a 3× concentration ofinhibitor were added, cells were incubated for 96 hours and then fixedfor 10′ with ice-cold isopropanol. Each condition was tested induplicate and average absorbance values were used for calculations. Thecells were washed twice with PBS, blocked with 5% non-fat dry milk inPBS+0.1% TRITON X100+0.02% SDS (PBSTS) and then incubated o/n at 4° C.with the 10E5/24 mab diluted in Milk/PBSTS. After washing 5 times withPBSTS, the cells were incubated for 3 hours at room temperature with Fcspecific anti-mouse IgG conjugated to alkaline phosphatase (Sigma),diluted in Milk/PBSTS. After washing again as above, the reaction wasdeveloped with p-Nitrophenyl phosphate disodium substrate (Sigma) andthe absorbance at 405/620 nm read at intervals. For calculations, weused data sets where samples incubated without inhibitors had absorbancevalues comprised between 1 and 1.5. The inhibitor concentration thatreduced by 50% the expression of NS3 (IC₅₀) was calculated by fittingthe data to the Hill equation,

Fraction inhibition=1−(Ai−b)/(A ₀ −b)=[I] ^(n)([I] ^(n) +IC ₅₀)

where:

-   -   Ai=absorbance value of HBI10 cells supplemented with the        indicated inhibitor concentration.    -   A₀=absorbance value of HBI10 cells incubated without inhibitor.    -   b=absorbance value of Huh-7 cells plated at the same density in        the same microtiter plates and incubated without inhibitor.    -   n=Hill coefficient.        (iii) General Procedures

All solvents were obtained from commercial sources (Fluka, puriss.) andwere used without further purification. With the exception of routinedeprotection and coupling steps, reactions were carried out under anatmosphere of nitrogen in oven dried (110° C.) glassware. Organicextracts were dried over sodium sulfate, and were concentrated (afterfiltration of the drying agent) on rotary evaporators operating underreduced pressure. Flash chromatography was carried out on silica gelfollowing published procedure (W. C. Still et al., J. Org. Chem. 1978,43, 2923) or on commercial flash chromatography systems (BIOTAGECorporation and JONES FLASHMASTER II) utilising pre-packed columns.

Reagents were usually obtained directly from commercial suppliers (andused as supplied) but a limited number of compounds from in-housecorporate collections were utilised. In the latter case the reagents arereadily accessible using routine synthetic steps that are eitherreported in the scientific literature or are known to those skilled inthe art.

¹H NMR spectra were recorded on BRUKER AM series spectrometers operatingat (reported) frequencies between 300 and 600 MHz. Chemical shifts (6)for signals corresponding to non-exchangeable protons (and exchangeableprotons where visible) are recorded in parts per million (ppm) relativeto tetramethylsilane and are measured using the residual solvent peak asreference. Signals are tabulated in the order: multiplicity (s, singlet;d, doublet; t, triplet; q, quartet; m, multiplet; br, broad, andcombinations thereof); coupling constant(s) in hertz (Hz); number ofprotons. Mass spectral (MS) data were obtained on a PERKIN ELMER API100, or WATERS MICROMASS ZQ, operating in negative (ES⁻) or positive(ES⁺) ionization mode and results are reported as the ratio of mass overcharge (m/z) for the parent ion only. Preparative scale HPLC separationswere carried out on a WATERS DELTA PREP 4000 separation module, equippedwith a WATERS 486 absorption detector or on a GILSON preparative system.In all cases compounds were eluted with linear gradients of water andacetonitrile both containing 0.1% TFA using flow rates between 15 and 40mL/min.

The following abbreviations are used in the examples, the schemes andthe tables: Ac: acetyl; aq.: aqueous; Ar: aryl; atm: atmosphere; cat.:catalytic; dioxan(e): 1,4-dioxane; dppf:(1,1′-bisdiphenylphosphino)ferrocene; 1,2-DCE: 1,2-dichloroethane; DCM:dichloromethane; DIPEA: diisopropylethyl amine; DMAP:N,N-dimethylpyridin-4-amine; DME: dimethoxyethane; DMF:dimethylformamide; DMS: dimethylsulfide; DMSO: dimethylsulfoxide; DMP:Dess-Martin Periodinane; EDAC.HCl:1-ethyl-(3-dimethylaminopropyl)carbodiimide HCl salt; eq.:equivalent(s); Et₃N: triethylamine; EtOAc: ethyl acetate; Et₂O: diethylether; EtOH: ethanol; Et₃SiH: triethylsilane; FC: Flash Chromatography;h: hour(s); HOAc: acetic acid; HATU:O-(7-azabenzotriazol-1-yl)-N,N,N′,NN′-tetramethyluroniumhexafluorophophate; Me: methyl; MeCN: acetonitrile; MeOH: methanol; min:minutes; MS: mass spectrum; NBS: N-bromo succinimide; PE: petroleumether; Ph: phenyl; quant.: quantitative; RP-HPLC: reversed phasehigh-pressure liquid chromatography; RT: room temperature; sat.:saturated; sec: second(s); SFC: Super-critical fluid chromatography;s.s.: saturated solution; TBAF: tetrabutyl ammonium fluoride; TBTU:O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate; TFA:trifluoroacetic acid; THF: tetrahydrofuran; THP: tetrahydropyranyl; TMS:trimethylsilyl.

EXAMPLE 116-cyclohexyl-3,6-dimethyl-17-phenyl-4,5,6,7,8,9-hexahydro-1H-13,15-(ethanediylidene)pyrrolo[2,1-f][1,2,7,10,13]thiatetraazacyclohexadecine-2,12(3H)-dione10,10-dioxide Step 1: methyl2-bromo-1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylate

A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate(prepared as described in published International patent application WO2004/087714, from commercially available methyl indole-6-carboxylate) inDMF (0.1 M) was treated with NaH (60% dispersion in mineral oil) (2 eq)at 0° C. The reaction was allowed to reach RT under a nitrogenatmosphere. Then tert-butyl-bromo acetate (3 eq) was added and thereaction was heated to 60° C. for 3 h. The reaction mixture was allowedto cool to RT, diluted with EtOAc and washed with an aqueous solution ofHCl (IN), brine and dried over Na₂SO₄ before being filtered and thesolvent volume reduced in vacuo. The product precipitated from theresidual solvent. The solid was collected and dried in vacuo to affordthe title compound (95%). (ES⁺) m/z 450 (M+H)⁺, 452 (M+H)⁺

Step 2: methyl1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylate

To a solution of methyl2-bromo-1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylatein dioxane (0.06 M) was added bis(triphenylphosphine)palladium(II)dichloride (0.2 eq) at RT under a nitrogen atmosphere. Then aqueousNa₂CO₃ (2 M; 4 eq) followed by phenylboronic acid (2.5 eq) were addedand the reaction was heated to 80° C. for 2 h. The reaction mixture wasallowed to cool and concentrated in vacuo. DCM was added and the organicphase washed with H₂O, brine and dried over Na₂SO₄ before being filteredand concentrated in vacuo. The crude material was purified by automatedFC (SiO₂; 95:5 EtOAc/PE) to afford the title compound (88%). (ES⁺) m/z448 (M+H)⁺

Step 3: [3-cyclohexyl-6-(methoxycarbonyl)-2-phenyl-1H-indol-1-yl]aceticacid

To methyl1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylatein DCM/H₂O (2:1; 0.15 M), TFA (>300 eq) were added at RT and thereaction left stirring for 1 h. The volatiles were removed in vacuo, andthe residue diluted with DCM. The organic phase was washed with brine,dried over Na₂SO₄, filtered and the solvent evaporated in vacuo toafford the title compound (98%). (ES⁺) m/z 392 (M+H)⁺

Step 4: methyl1-{2-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]-2-oxoethyl}-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylate

To a solution of[3-cyclohexyl-6-(methoxycarbonyl)-2-phenyl-1H-indol-1-yl]acetic acid inDCM (0.04 M), DIPEA (3 eq), tert-butylmethyl[2-(methylamino)ethyl]carbamate (2 eq) (prepared as described inEuropean patent application EP0296811, from commercially availableavailable N,N-dimethylethylenediamine) and HATU (2 eq) were added andthe mixture stirred at RT for 2 h. The solution was diluted with DCM andwashed with a saturated aqueous solution of NH₄Cl, a saturated aqueoussolution of NaHCO₃ and brine before being dried over Na₂SO₄, filteredand concentrated in vacuo. The crude was then used in the next stepwithout any further purification. (ES⁺) m/z 562 (M+H)⁺

Step 5:1-{2-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]-2-oxoethyl}-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylicacid

The crude methyl1-{2-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]-2-oxoethyl}-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylatein dioxane/H₂O/MeOH solution (1:1:1; 0.06 M) was treated with an aqueoussolution of KOH (5N) (3 eq). The solution was stirred at 60° C. for 4 h.The volume of the solution was reduced in vacuo, and the mixtureacidified with HCl (1N) before extracting with EtOAc (2×). The combinedorganic fractions were washed with brine, before being dried overNa₂SO₄, filtered and concentrated in vacuo. The crude was then used inthe next step without any further purification. (ES⁺) m/z 548 (M+H)⁺

Step 6: N-benzyl-3-chloropropane-1-sulfonamide

3-chloro-propylsulfonyl chloride was added dropwise to a stirredsolution of benzylamine (1 eq) and triethylamine (1.1 eq) in DCM (0.6 M)at 0° C. The solution was stirred at RT overnight. The solvent was thenremoved in vacuo, Et₂O was added to get a precipitate that waseliminated by filtration, while the filtrate was concentrated in vacuo.Subsequent addition of PE resulted in the formation of a whiteprecipitate that was collected by filtration to afford the titlecompound (86%). ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 2.02-2.09 (m, 2H),3.03-3.07 (m, 2H), 3.67 (t, J 6.6, 2H), 4.14 (d, J 6.1, 2H), 7.25-7.30(m, 1H), 7.32-7.36 (m, 4H), 7.73 (t, J 6.1, 1H).

Step 7: tert-butyl{2-[{[6-({benzyl[(3-chloropropyl)sulfonyl]amino}carbonyl)-3-cyclohexyl-2-phenyl-1H-indol-1-yl]acetyl}(methyl)amino]ethyl}methylcarbamate

A solution of the crude1-{2-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]-2-oxoethyl}-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylicacid in DCM (0.04 M) was treated with DMAP (2.5 eq),N-benzyl-3-chloropropane-1-sulfonamide (1.5 eq) and EDAC.HCl (1.5 eq).The reaction was left stirring at 40° C. overnight. Further DMAP (2.5eq), N-benzyl-3-chloropropane-1-sulfonamide (1.5 eq) and EDAC.HCl (1.5eq) were added and the reaction left to stir at 40° C. for anothernight. The mixture was diluted with DCM and washed with an aqueoussolution of HCl (1N), a saturated aqueous solution of NaHCO₃ and brinebefore being dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude was then used in the next step without any further purification.(ES⁺) m/z 777 (M+H)⁺

Step 8:N-benzyl-N-[(3-chloropropyl)sulfonyl]-3-cyclohexyl-1-(2-{methyl[2-(methylamino)ethyl]amino}-2-oxoethyl)-2-phenyl-1H-indole-6-carboxamidehydrochloride

A solution of the crude tert-butyl{2-[{[6-({benzyl[(3-chloropropyl)sulfonyl]amino}carbonyl)-3-cyclohexyl-2-phenyl-1H-indol-1-yl]acetyl}(methyl)amino]ethyl}methylcarbamatein DCM) (0.09 M) was treated with TFA (140 eq) at 0° C. The reaction wasallowed to reach RT in about 1 h. The solvent was then removed in vacuo,a 2 M solution HCl in Et₂O was added and the volatiles removed in vacuo.Acetonitrile was added and the precipitate was collected by filtrationto afford clean compound (30%). (ES⁺) m/z 677 (M+H)⁺

Step 9:16-cyclohexyl-3,6-dimethyl-17-phenyl-4,5,6,7,8,9-hexahydro-1H-13,15-(ethanediylidene)pyrrolo[2,1-f][1,2,7,10,13]thiatetraazacyclohexadecine-2,12(3H)-dione10,10-dioxide

DIPEA (40 eq) was added toN-benzyl-N-[(3-chloropropyl)sulfonyl]-3-cyclohexyl-1-(2-{methyl[2-(methylamino)ethyl]amino}-2-oxoethyl)-2-phenyl-1H-indole-6-carboxamidehydrochloride in DMF (0.007 M). The reaction mixture was heated in amicrowave system at 180° C. for 2800 s. Then 10% Pd/C, (1:1weight:weight with respect to substrate) was added and the reactionstirred under a hydrogen atmosphere overnight. The reaction was flushedwith N₂, filtered and concentrated in vacuo. The crude was then purifiedby automated RP-HPLC (stationary phase: column SYMMETRY PREP. C18, 7 μm,19×300 mm. Mobile phase: acetonitrile/H₂O buffered with 0.1% TFA).Fractions containing the pure compound were combined and freeze dried toafford the title compound as a white powder (24%). ¹H NMR (500 MHz,DMSO-d₆+TFA, 292 K) δ 1.16-1.32 (m, 3H), 1.64-2.11 (m, 9H), 2.57-2.60(m, 1H), 2.84 (s, 3H), 3.12 (s, 3H), 3.19-3.31 (m, 4H), 3.44-3.60 (m,3H), 3.73-3.82 (m, 1H), 4.82-4.92 (m, 2H), 7.23-7.42 (m, 2H), 7.43-7.61(m, 4H), 7.86-7.91 (m, 2H), 8.90-9.11 (b s, 1H); (ES⁺) m/z 551 (M+H)⁺

The following tables contain further examples:

TABLE 1 16-membered macrocycles Example m/z no. Compound name Structureprocedure (ES⁺) 1≡10116-cyclohexyl-3,6-dimethyl-17-phenyl-4,5,6,7,8,9-hexahydro-1H-13,15-(ethanediylidene)pyrrolo[2,1-f][1,2,7,10,13]thiatetraazacyclohexadecine-2,12(3H)-dione10,10-dioxide

B 551

TABLE 2 17-membered macrocycles Example m/z no. Compound name Structureprocedure (ES⁺) 20117-cyclohexyl-3,6-dimethyl-18-phenyl-3,4,5,6,7,8,9,10-octahydro-14,16-(ethanediylidene)pyrrolo[2,1-f][1,2,7,10,13]thiatetraazacycloheptadecine-2,13-dione11,11-dioxide

B 565

1. A compound of the formula (I):

wherein Ar is a moiety containing at least one aromatic ring andpossesses 5-, 6-, 9- or 10-ring atoms optionally containing 1, 2 or 3heteroatoms independently selected from N, O and S, which ring isoptionally substituted by groups Q¹ and Q²; Q¹ is halogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, aryl, heteroaryl, CONR^(a)R^(b),(CH₂)₀₋₃NR^(a)R^(b), O(CH₂)₁₋₃NR^(a)R^(b), O(CH₂)₀₋₃CONR^(a)R^(b),O(CH₂)₀₋₃aryl, O(CH₂)₀₋₃heteroaryl, O(CR^(e)R^(f))aryl,O(CR^(e)R^(f))heteroaryl or OCHR^(c)R^(d); R^(a) and R^(b) are eachindependently selected from hydrogen, C₁₋₄alkyl and C(O)C₁₋₄alkyl; orR^(a), R^(b) and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms, where said ring is optionallysubstituted by halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; R^(c) andR^(d) are each independently selected from hydrogen and C₁₋₄alkoxy; orR^(c) and R^(d) are linked by a heteroatom selected from N, O and S toform a heteroaliphatic ring of 4 to 7 ring atoms, where said ring isoptionally substituted by halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; andwherein said C₁₋₄alkyl, C₁₋₄alkoxy and aryl groups are optionallysubstituted by halogen or hydroxy; R^(e) is hydrogen or C₁₋₆alkyl; R^(f)is C₁₋₆alkyl; Q² is halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy, wheresaid C₁₋₄alkyl and C₁₋₄alkoxy groups are optionally substituted byhalogen or hydroxy; or Q¹ and Q² may be linked by a bond or a heteroatomselected from N, O and S to form a ring of 4 to 7 atoms, where said ringis optionally substituted by halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy;A is C₃₋₆alkyl or C₂₋₆alkenyl, or A is a non-aromatic ring of 3 to 8ring atoms where said ring may contain a double bond and/or may containa O, S, SO, SO₂ or NH moiety, or A is a non-aromatic bicyclic moiety of4 to 8 ring atoms, and A is optionally substituted by halogen, hydroxy,C₁₋₄alkyl or C₁₋₄alkoxy; D is N or CR^(g); R⁸ is hydrogen, fluorine,chlorine, C₁₋₄alkyl, C₂₋₄alkenyl or C₁₋₄alkoxy, where said C₁₋₄alkyl,C₂₋₄alkenyl and C₁₋₄alkoxy groups are optionally substituted by hydroxyor fluorine; W is a bond, C═O, O, S(O)₀₋₂ or —(CR¹⁰R¹¹)—(CR¹²R¹³)₀₋₁—; Xis C═O, O, —CR¹⁴R¹⁵— or NR¹⁴; R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are eachindependently selected from hydrogen, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl,C₁₋₆alkoxy, C(O)C₁₋₆alkyl, (CH₂)₀₋₃aryl, (CH₂)₀₋₃heteroaryl,(CH₂)₀₋₃Het, (CH₂)₀₋₃NR¹⁶R¹⁷, C(O)(CH₂)₀₋₃NR¹⁶R¹⁷,NHC(O)(CH₂)₀₋₃NR¹⁶R¹⁷, O(CH₂)₁₋₃NR¹⁶R¹⁷, S(O)₀₋₂(CH₂)₀₋₃R¹⁶R¹⁷ andC(O)(CH₂)₀₋₃OR¹⁶; or R¹⁴ is linked to R² or R²³ to form a ring of 4 to10 atoms, where said ring is optionally substituted by halogen,hydrogen, C₁₋₄alkyl or C₁₋₄alkoxy; Het is a heteroaliphatic ring of 4 to7 ring atoms, which ring may contain 1, 2 or 3 heteroatoms selected fromN, O or S or a group S(O), S(O)₂, NH or NC₁₋₄alkyl; R¹⁶ and R¹⁷ areindependently selected from hydrogen, C₁₋₆alkyl and (CH₂)₀₋₄NR¹⁸R¹⁹; orR¹⁶, R¹⁷ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms, which ring may optionallycontain 1 or 2 more heteroatoms selected from O or S or a group S(O),S(O)₂, NH or NC₁₋₄alkyl, and which ring is optionally substituted byhalogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; R¹⁸ and R¹⁹ are independentlyselected from hydrogen and C₁₋₆alkyl; or R¹⁸, R¹⁹ and the nitrogen atomto which they are attached form a heteroaliphatic ring of 4 to 7 ringatoms, which ring may optionally contain 1 or 2 more heteroatomsselected from O or S or a group S(O), S(O)₂, NH or NC₁₋₄alkyl, and whichring is optionally substituted by halogen, hydroxy, C₁₋₄alkyl orC₁₋₄alkoxy; R¹ is hydrogen or C₁₋₆alkyl; B is —CR²⁰R²¹—, —C(═O)—, —SO—or —SO₂—; R²⁰ and R²¹ are independently selected from hydrogen andC₁₋₆alkyl; or R²⁰ and R²¹, together with the carbon atom to which theyare joined, form a C₃₋₆cycloalkyl group; M is C₄₋₈alkylene orC₄₋₈alkenylene, optionally substituted by R²², where 1, 2 or 3 of thecarbon atoms in the C₄₋₈alkylene or C₄₋₈alkenylene groups is optionallyreplaced by O, NR²³, S, SO, SO₂, aryl, heteroaryl or Het, where R²³ ishydrogen or C₁₋₆alkyl, or R²³ is linked to R¹⁴ to form a ring of 4 to 10atoms as hereinbefore described; where R²² is halo, C₁₋₄alkyl,(CH₂)₀₋₃C₃₋₈cycloalkyl, (CH₂)₀₋₃aryl, heteroaryl, Het or oxo, or R²² islinked to R¹⁴ to form a ring of 4 to 10 atoms as hereinbefore described;and pharmaceutically acceptable salts thereof.
 2. A compound accordingto claim 1 in which Ar is selected from phenyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, furanyl, pyrazolyl, imidazolyl and thienyl,which ring is optionally substituted by groups Q¹ and Q² as definedaccording to claim
 1. 3. A compound according to claim 2 in which Q¹ isfluorine, chlorine, methyl or methoxy and Q² is absent.
 4. A compoundaccording to claim 1 in which A is cyclopentyl or cyclohexyl, optionallysubstituted by halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy.
 5. A compoundaccording to claim 4 in which A is unsubstituted.
 6. A compoundaccording to claim 1 in which D is CR^(g) where R^(g) is hydrogen orC₁₋₄alkyl.
 7. A compound according to claim 1 in which W is —CH₂— or—CH₂CH₂—.
 8. A compound according to claim 1 in which X is C═O or —CH₂—.9. A compound according to claim 1 in which R¹ is hydrogen or methyl.10. A compound according to claim 1 in which B is —CH₂— or —SO₂—.
 11. Acompound according to claim 1 in which M is selected from:


12. A compound according to claim 1 selected from:16-cyclohexyl-3,6-dimethyl-17-phenyl-4,5,6,7,8,9-hexahydro-1H-13,15-(ethanediylidene)pyrrolo[2,1-f][1,2,7,10,13]thiatetraazacyclohexadecine-2,12(3H)-dione10,10-dioxide,17-cyclohexyl-3,6-dimethyl-18-phenyl-3,4,5,6,7,8,9,10-octahydro-14,16-(ethanediylidene)pyrrolo[2,1-f][1,2,7,10,13]thiatetraazacycloheptadecine-2,13-dione11,11-dioxide, and pharmaceutically acceptable salts thereof.
 13. Acompound according to claim 1 of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein W, X and M are asdefined according to claim
 1. 14. A pharmaceutical compositioncomprising an effective amount of a compound of the formula (I), or apharmaceutically acceptable salt thereof, according to claim 1 and apharmaceutically acceptable carrier.
 15. A method of inhibitinghepatitis C virus polymerase and/or of treating or preventing an illnessdue to hepatitis C virus, the method involving administering to a humanor animal (preferably mammalian) subject suffering from the condition atherapeutically or prophylactically effective amount of thepharmaceutical composition described above or of a compound of formula(I) according to claim 1, or a pharmaceutically acceptable salt thereof.